Subclinical Hyperthyroidism Is a Risk Factor for Poor Functional Outcome After Ischemic Stroke
Background and Purpose—Subclinical hyperthyroidism is associated with adverse cardiovascular events, including stroke and atrial fibrillation. However, its impact on functional outcome after stroke remains unexplored.
Methods—A total of 165 consecutively recruited patients admitted for ischemic stroke were included in this observational prospective study. Blood samples were taken in the morning within 3 days after symptom onset, and patients were divided into the following 3 groups: subclinical hyperthyroidism (0.1< thyroid-stimulating hormone ≤0.44 μU/mL), subclinical hypothyroidism (2.5≤ thyroid-stimulating hormone <20 μU/mL), and euthyroid state (0.44< thyroid-stimulating hormone <2.5 μU/mL). Patients with overt thyroid dysfunction were excluded. Follow-up took place 3 months after stroke. Primary outcome was functional disability (modified Rankin Scale), and secondary outcome was level of dependency (Barthel Index). Ordinal logistic regression analysis was used to adjust for possible confounders. Variables previously reported to be affected by thyroid function, such as atrial fibrillation, total cholesterol, or body mass index, were included in an additional model.
Results—Nineteen patients (11.5%) had subclinical hyperthyroidism, and 23 patients (13.9%) had subclinical hypothyroidism. Patients with subclinical hyperthyroidism had a substantially increased risk of functional disability 3 months after stroke compared with subjects with euthyroid state (odds ratio, 2.63; 95% confidence interval, 1.02–6.82, adjusted for age, sex, smoking status, and time of blood sampling). The association remained significant, when including the baseline NIHSS, TIA, serum CRP, atrial fibrillation, body mass index, and total cholesterol as additional variables (odds ratio, 3.95; 95% confidence interval, 1.25–12.47), and was confirmed by the secondary outcome (Barthel Index: odds ratio, 9.12; 95% confidence interval, 2.08–39.89).
Conclusions—Subclinical hyperthyroidism is a risk factor for poor outcome 3 months after ischemic stroke.
With an estimated prevalence of ≈2%, subclinical hyperthyroidism is common in the general population, varying in frequency with age, sex, and nutrition factors.1 It is associated with various cardiovascular effects and conditions, including a higher heart rate,2 an increase of left-ventricular mass,1 and atrial fibrillation (AF).3 Subclinical hyperthyroidism has further been shown to increase the risk for carotid plaques and prevalent stroke.4 Although subclinical hypothyroidism has been associated with favorable outcome after acute ischemic stroke,5,6 the effects of subclinical hyperthyroidism on functional outcome have not been investigated. Therefore, we studied the effects of subclinical thyroid dysfunction on functional outcome 3 months after acute ischemic stroke, considering euthyroid state as a reference.
Patients were recruited through an observational single-center cohort study following Institutional Review Board approval by the medical faculty of the Ludwig-Maximilians- Universität-München. Inclusion criterion was an acute ischemic stroke defined by a new focal neurological deficit with a corresponding lesion on MR- or delayed computed tomography scan. Exclusion criteria were known thyroid disease, biochemically defined overt thyroid disease, time since symptom onset >72 hours, and use of thyroid-affecting medication. Patients received 72-hour ECG monitoring at baseline and 12-channel ECG monitoring at follow-up.
Blood samples were drawn between 6 and 9 am. Serum thyroid–stimulating hormone, free thyroxine (fT4), and free tri–iodothyronine (fT3) concentrations were quantified using a chemiluminescence-based immunoassay.7 Because clinical symptoms of mild thyroid diseases are nonspecific, thyroid state was biochemically defined using published criteria.5,8
The modified Rankin Scale measured 3 months after stroke was used as the primary functional outcome measure. The Barthel Index was used as a supporting measure to assess consistency in direction of effect.9
Associations between thyroid-stimulating hormone and functional outcomes were determined using ordinal logistic regression with euthyroid state as a reference.9 To avoid inappropriately small patient numbers within individual cells, modified Rankin Scale scores were categorized into 3 groups: 0 to 1, 2 to 3, and 4 to 6. Adjusted associations were calculated to investigate confounding and direct effects. All analyses were 2-sided, conducted at a 0.05 level of significance, and carried out using SAS version 9.3. Detailed Methods are described in the online-only Data Supplement.
Baseline characteristics of the study population are shown in Table 1. Patients with subclinical hyperthyroidism had a lower body mass index and lower blood lipid levels compared with patients with euthyroid state. AF was more common in patients with subclinical hyperthyroidism and hypothyroidism compared with patients with euthyroid state.
Stroke recurrences occurred in 1 patient (5.3%) with subclinical hyperthyroidism, in 6 patients (4.9%) with euthyroid state, and in none of the patients with subclinical hypothyroidism. One patient with subclinical hyperthyroidism and 4 patients with euthyroid state died during follow-up (Figure). Subclinical hyperthyroidism was associated with a significantly higher risk of poor functional outcome in both statistical models (Table 2). Subclinical hypothyroidism was associated with a lower risk of poor functional outcome, although the association was not significant (Table 2).
This study demonstrates that subclinical hyperthyroidism is an independent risk factor for poor functional outcome 3 months after ischemic stroke. Our findings must be interpreted in the context of recent studies that have shown multiple effects of subclinical thyroid disease on the cardiovascular system.1 Subclinical hyperthyroidism increases the risk of AF3 and cardioembolic stroke, which has a less favorable short-term outcome than other stroke subtypes.10 In the current study, AF was more common in patients with subclinical hyperthyroidism than in patients with euthyroid state. However, the association with poor outcome remained significant after adjustment for AF, and AF was likewise more common in patients with subclinical hypothyroidism, which showed a favorable effect on outcome in this and in earlier studies.5,6
Long-lasting subclinical hyperthyroidism has been associated with heart failure.2 None of our patients showed signs of heart failure, but cardiac function was not quantitatively assessed and therefore cannot be excluded as a contributing factor. Other mechanisms to be considered are changes in coagulation parameters11 and an increased sympathetic nervous system tone.12 Elevated concentrations of thyroid hormones are associated with an increase in energy and oxygen demand,12 which would be expected to impair ischemic tolerance in the brain. However, more detailed studies are required to determine the impact of thyroid function on cerebral ischemia.
Serum thyroid-stimulating hormone reference limits remain a matter of debate. This in part relates to the impact of age, sex, ethnicity, diurnal variations, and acute illnesses.1 In the current study, we accounted for these factors by standardized blood sampling by excluding patients with symptom onset >72 hours and by including age, sex, and time of blood sampling in our statistical models. Limitations of this study include the relatively small number of patients with subclinical thyroid disease, a potential bias toward recruitment of less severely affected patients, and that the outcome had to be assessed by telephone interviews in some patients. Also, we did not perform systematic imaging on the thyroid gland.
Our findings contribute to the growing evidence for adverse effects resulting from subclinical hyperthyroidism.1 Although significant for both end points, our findings require confirmation in additional cohorts.
The authors thank M. Deschner, A. Dörr, T. Hasselwander, A. Zollver, and M. Vogeser for their support.
Sources of Funding
This work was supported by Vascular Dementia Research Foundation.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.000833/-/DC1.
- Received January 18, 2013.
- Accepted February 11, 2013.
- © 2013 American Heart Association, Inc.
- Biondi B
- Dörr M,
- Empen K,
- Robinson DM,
- Wallaschofski H,
- Felix SB,
- Völzke H
- Lees KR,
- Bath PM,
- Schellinger PD,
- Kerr DM,
- Fulton R,
- Hacke W,
- et al
- Lavados PM,
- Sacks C,
- Prina L,
- Escobar A,
- Tossi C,
- Araya F,
- et al